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A Comprehensive Review of Pegvaliase, an Enzyme Substitution Therapy for the Treatment of Phenylketonuria

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A Comprehensive Review of Pegvaliase, an Enzyme Substitution Therapy for the Treatment of Phenylketonuria University of Massachusetts Medical School eScholarship@UMMS Open Access Articles Open Access Publications by UMMS Authors 2019-06-21 A Comprehensive Review of Pegvaliase, an Enzyme Substitution Therapy for the Treatment of Phenylketonuria Tasmina Hydery University of Massachusetts Medical School Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/oapubs Part of the Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Enzymes and Coenzymes Commons, Medicinal and Pharmaceutical Chemistry Commons, Nervous System Diseases Commons, Nutritional and Metabolic Diseases Commons, and the Therapeutics Commons Repository Citation Hydery T, Coppenrath VA. (2019). A Comprehensive Review of Pegvaliase, an Enzyme Substitution Therapy for the Treatment of Phenylketonuria. Open Access Articles. https://doi.org/10.1177/ 1177392819857089. Retrieved from https://escholarship.umassmed.edu/oapubs/3877 Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Open Access Articles by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. DTI0010.1177/1177392819857089Drug Target InsightsHydery and Coppenrath 857089review-article2019 Drug Target Insights A Comprehensive Review of Pegvaliase, an Enzyme Volume 13: 1–8 © The Author(s) 2019 Substitution Therapy for the Treatment of Article reuse guidelines: sagepub.com/journals-permissions Phenylketonuria DOI:https://doi.org/10.1177/1177392819857089 10.1177/1177392819857089 Tasmina Hydery1 and Valerie Azzopardi Coppenrath2 1Department of Family Medicine and Community Health, UMass Medical School—Clinical Pharmacy Services (CPS), Shrewsbury, MA, USA. 2School of Pharmacy—Worcester/Manchester, Massachusetts College of Pharmacy and Health Sciences (MCPHS) University, Worcester, MA, USA. ABSTRACT OBJectIVE: To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of a phenylalanine-metabolizing enzyme indicated to reduce blood phenylalanine concentrations, pegvaliase injection. Data soUrces: Searches of MEDLINE (1946-September 1, 2018) were conducted using the terms pegvaliase and phenylalanine ammo- nia lyase (PAL). Additional data were obtained from the prescribing information, the product dossier obtained from the manufacturer, and Clinicaltrials.gov. STUDY seLectION AND data EXtractION: All English language articles related to pharmacology, pharmacokinetics, efficacy, or safety of the combination therapy in human subjects were reviewed. Data SYNTHesIS: Pegvaliase is a pegylated PAL enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. Blood pheny- lalanine levels were reduced by approximately 50% to 70% in patients receiving therapeutic doses of pegvaliase. However, most patients experienced adverse events. CONCLUSIONS AND reLEVANce: The mainstay of therapy in phenylketonuria (PKU) has historically consisted of dietary restriction of phenylalanine. Pegvaliase injection is the first Food and Drug Administration (FDA)–approved enzyme substitution therapy for patients with PKU. The therapy may be a viable option for patients with documented blood phenylalanine >600 µmol/L who have failed existing manage- ment strategies. KEYWords: Palynziq, pegvaliase, phenylalanine ammonia lyase, pegvaliase-pqpz, phenylketonuria, PKU RECEIVED: May 22, 2019. ACCEPTED: May 23, 2019. DecLaratION of coNFLIctING INterests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this TYPE: Review article. FUNDING: The author(s) received no financial support for the research, authorship, and/or CORRESPONDING AUTHOR: Tasmina Hydery, Department of Family Medicine and publication of this article. Community Health, UMass Medical School—Clinical Pharmacy Services (CPS), Shrewsbury, MA 01545, USA. Email: [email protected] Introduction 360 µmol/L4,5 or 120 to 600 µmol/L, (van Wegberg, MacDonald Phenylketonuria (PKU) is a rare autosomal recessive condition and Ahring, 2017) therapy must be individualized to each patient. affecting about 1 in 13 500 to 19 000 people in the United Management of patients with HPA and PKU should be States.1 Phenylketonuria is diagnosed through detection of provided by an interdisciplinary team of nutritionists, elevated blood phenylalanine concentration.2 If untreated, psychologists, social workers, and metabolic specialists.2 PKU can cause chronic intellectual, neurodevelopmental, and Phenylketonuria is a relatively rare disease and patients may psychiatric disabilities. Excessive phenylalanine is thought to require lifelong treatment. The goal of therapy is to lower interfere with brain growth, myelination, and neurotransmitter blood phenylalanine concentrations to minimize the neuro- synthesis. Most cases of PKU are detected shortly after birth by cognitive and psychiatric effects of PKU.4–7 The mainstay of newborn screening. As a result, the severe signs and symptoms therapy is dietary restriction of phenylalanine and supplemen- of classic PKU are rarely seen.2 tation with phenylalanine-free medical foods to avoid nutri- Elevated phenylalanine levels are caused by a deficiency in the tional deficits.4–6 The medical foods are protein substitutes enzyme, phenylalanine hydroxylase (PAH).2 The spectrum of that are phenylalanine-free and fortified in tyrosine and may severity in untreated PKU ranges from complete enzyme defi- contain glycomacropeptides and other large neutral amino ciency or classic PKU (phenylalanine concentration > 1200 µmol/L), acids as the protein source.3 Adherence to the restrictive diet moderate PKU (phenylalanine concentration = 900-1200 µmol/L), requires planning and organization, and can be challenging for mild PKU (phenylalanine concentration = 600-900 µmol/L), and patients.4 mild hyperphenylalaninemia (HPA) (phenylalanine concentra- Sapropterin was Food and Drug Administration (FDA)– tion = 360-600 µmol/L).3 Although guidelines recommend life- approved on December 13, 2007, and was the first pharmaco- long treatment to a target blood phenylalanine level of 120 to logic therapy for treatment of PKU.8 It is an oral PAH cofactor Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Drug Target Insights Table 1. Summary of pharmacokinetic parameters studied. PharmacOKINETIC parameter DAILY MAINTENANCE DOsaGE PEGvaLiase 20 MG PEGvaLiase 40 MG Median Tmax 8 hours Cmax at steady state (mean ± SD) 14.0 ± 16.3 mg/L 16.7 ± 19.5 mg/L Apparent volume of distribution (mean ± SD) 26.4 ± 64.8 L 22.2 ± 19.7 L Apparent clearance at steady state (mean ± SD) 0.39 ± 0.87 L/h 1.25 ± 2.46 L/h Half-life (mean ± SD) 47 ± 42 hours 60 ± 45 hours Steady state plasma concentrations during maintenance treatment (mean ± SD) 11.2 ± 9.0 mg/L 10.4 ± 12.7 mg/L Metabolism Catabolic pathways, degraded into small peptides and amino acids Abbreviations: Cmax, peak concentration; Tmax, time to peak concentration. indicated to reduce blood phenylalanine concentrations in Data Synthesis patients with HPA due to tetrahydrobiopterin (BH4)- Pharmacology responsive PKU. Sapropterin is used in conjunction with a phenylalanine-restricted diet.9 The efficacy of sapropterin is PAH catalyzes the irreversible conversion of phenylalanine based on the presence of residual PAH enzymatic activity. to tyrosine. In the absence of PAH in PKU, dietary phenyla- Approximately 25% to 50% of patients with PKU respond to lanine is unable to be converted to tyrosine and undergoes sapropterin.4 further processing to metabolites including L-dopa, thyrox- 13 Phase 3 trials for an enzyme substitution therapy for ine, dopamine, noradrenaline, adrenaline, and melanin. PKU began in 2013 and showed promise to be effective in There are 2 modes of enzyme therapy through replacement any patient with PKU regardless of residual enzymatic of the PAH enzyme or substitution with another enzyme to 12 activity.4 Pegvaliase, FDA-approved on May 24, 2018, acts degrade excess phenylalanine. Pegvaliase follows the latter as a substitute for the deficient PAH enzyme.10 Pegvaliase category and is a pegylated PAL enzyme that converts phe- 8 is indicated to reduce blood phenylalanine concentrations nylalanine to ammonia and trans-cinnamic acid. Ammonia in adult patients with PKU who have uncontrolled blood is metabolized by the liver. Trans-cinnamic acid and its final phenylalanine concentrations >600 µmol/L on existing product, benzoic acid, are conjugated with glycine and 13,14 management.11,12 excreted in the urine. Adult patients with PKU whose phenylalanine levels are not appropriately managed may experience adverse neurocog- Pharmacokinetics nitive and psychiatric outcomes.7 The objective of this article is Due to the heterogeneity of immune response in adults with to review the pharmacology, pharmacokinetics, efficacy, safety, PKU, the pharmacokinetics of pegvaliase exhibit high interpa- and place in therapy of pegvaliase injection. It will also provide
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